Method for convection enhanced therapeutic delivery

ABSTRACT

A system for convection enhanced delivery of therapeutic comprises one or more flexible, biocompatible microcatheters that are directed to a target location to deliver a therapeutic agent. The microcatheter is releasably coupled to a guide tube and directed to the desired location. The microcatheters are small and flexible in order to reach the target areas, minimize trauma at the injection site, and minimize reflux of the injectable therapeutic.

RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional patentapplication Ser. No. 12/123,031, entitled “Apparatus and Method forConvection Enhanced Therapeutic Delivery,” filed on May 19, 2008, whichapplication claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application No. 60/938,784, entitled “ConvectionEnhanced Delivery System,” filed May 18, 2007, each of which is hereinincorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention is related to convection enhanced delivery of atherapeutic for treatment of tumors, more specifically, treating tumorsin the brain.

BACKGROUND

Malignancies of the brain are among the most devastating diseases known.In the US, the prevalence of brain cancer is 360,000, with 15,000 deathsper year. A large percentage of these malignancies are found to beglioblastoma multiforme (GBM), having a very rapid, aggressive, anduncontrolled growth. Very little progress has been made in the treatmentof GBM over the past 25 years. Present therapeutic approaches involvesurgical excision, chemotherapy, and radiation therapy. The death rateof patients who have been diagnosed as having GBM, however, is 98%.Patients rarely survive for more than one year from diagnosis, oftendying within six months. There is on-going research in how toeffectively treat GBM.

One experimental approach is “targeted toxin therapy,” in whichchemotherapeutics are directly infused into the tumor and thesurrounding tissue where the tumor cells begin to infiltrate. Thismethod, while requiring a surgical procedure, has been shown to reducethe debilitating side effects seen with systemic administration. It alsoreduces concerns regarding medicine crossing the blood brain barrier(BBB), and may achieve very high concentrations of therapeutic agentdirectly within, and in the vicinity of, the tumor.

Numerous agents for targeted toxin therapy are currently in clinicaldevelopment. One such targeted toxin is cintredekin besudotox (CB),which is a recombinant protein made up of interleukin-13 and an activetoxic protein derived from Pseudomonas exotoxin TP-38. CB bindsselectively to the IL-13-overexpressing malignant glioma cells. Otheragents being evaluated include standard anti-mitotic chemotherapyagents, transferrin-conjugated toxins, and radioisotope conjugates.

A delivery method for these medicines currently being evaluated is knownas “convection-enhanced delivery” (CED), in which the tumor andsurrounding tissue are deluged with high volumes of therapeutic agentunder positive pressure. This method was designed by NIH researchers tofacilitate the infiltration into brain tissue of high molecular weighttherapeutic molecules that would not ordinarily diffuse over appreciabledistances if simply injected. The parameters for effective CED have beenextensively studied and modeled.

Delivery devices to accomplish CED remain under development. Presently,large bore catheters are surgically placed within the malignant mass andan infusion pump is used to drive flow at a rate of approximately 3 mLper hour for extended periods, e.g., up to 4 days. Various cathetershave been designed and tested, usually having outer diameters (OD) of 1mm or greater. Human CED trials are being performed using ventricularshunt tubing (2.1 mm OD) or spinal drains, e.g., 18 gauge, or 1.2 mm indiameter, as delivery cannulas.

These CED delivery methods have a number of shortcomings associated withthe size of the delivery catheters. Under high-flow conditions, backflow(or reflux) of the injectable therapeutic occurs in a proximal directionalong the outer catheter walls, resulting in a loss of the therapeuticinto spaces and regions where it is not intended, and a loss of thepressure required to enable convection of the therapeutic moleculeswithin an interstitial space. These shortcomings are particularlyproblematic in situations where the tumor is more superficial, as thesegment of catheter that is surrounded by brain tissue is reduced. Fortargets that are deep within the brain, the length of catheter that issurrounded by tissue is increased, and the resistance to back flow is,therefore, also increased. To mitigate this situation, surgery isplanned so that the cannula trajectory traverses the longest possibletrack through the parenchyma to minimize reflux. It has been observed,however, that the larger diameter catheters do not permit preciseplacement, which is an issue as it is required for more targeted ordiscrete delivery. Moreover, inserting multiple larger catheters iscumbersome and may limit wide distribution of the therapeutic.

Smaller diameter catheters have been shown to decrease backflow becausethe amount of backflow decreases as a function of the catheter diameterto the power of four-fifths.

Smaller diameter catheters have less rigidity, therefore, they haverequired construction in a telescoping, or “step design,” in order toobtain a final catheter diameter of approximately 0.168 mm. Knowntelescope designs use smaller diameter tubing glued to the end of arigid stainless steel cannula. The rigid tube, however, is problematicfor situations in which it must be left in place, e.g., in the brain,for extended periods of time measured in hours or days. The rigidportion presents a risk to the patient due to, for example, accidentalcontact and/or movement. Furthermore, while a final diameter of 0.168 mmminimizes reflux, the rate of delivery may be compromised.

SUMMARY

In one embodiment, an apparatus for delivering a therapeutic to alocation in a body comprises: a hollow guide tube comprising a lumentherethrough with distal and proximal openings, the guide tubecomprising an outer diameter in a range of 0.5 to 1.2 mm; a stylet,having proximal and distal portions, disposed within the guide tubelumen, wherein the stylet distal portion extends distally from the guidetube distal opening; a catheter having a catheter lumen running from adistal opening to a proximal opening, the catheter lumen having adiameter in a range of 0.03 to 2.11 mm; and a loop attached to acatheter distal portion, the loop releasably coupled to the styletdistal portion.

In another embodiment, a method of delivering a therapeutic to a targetregion in a body, the method comprises: providing a hollow guide tubecomprising a lumen therethrough with distal and proximal openings, theguide tube having an outer diameter in a range of 0.5 mm to 1.2 mm;disposing a stylet, having proximal and distal portions, within theguide tube lumen, and extending the stylet distal portion distally fromthe guide tube distal opening; providing a catheter having a distalportion and releasably coupling the catheter distal portion to thestylet distal portion, the catheter comprising a catheter lumen having adiameter in a range of 0.03 mm to 2.11 mm and running from a distalopening to a proximal opening; distally inserting the releasably coupledguide tube, stylet and catheter into the body and locating the distalportion of the catheter in the target region; withdrawing the styletproximally through the tube and releasing the catheter from the stylet;withdrawing the guide tube from the body and leaving the distal openingof the catheter in the target region; coupling the catheter to a sourceof the therapeutic; and delivering the therapeutic to the target regionthrough the catheter.

In one embodiment, a method of delivering a therapeutic to a targetregion in a body comprises: providing a catheter having a catheter lumenhaving a diameter in a range of 0.03 mm to 2.11 mm and running from adistal opening to a proximal opening; disposing a stylet within thecatheter lumen; distally inserting the coupled stylet and catheter intothe body and locating the distal opening of the catheter in the targetregion; withdrawing the stylet proximally through the catheter andleaving the distal opening of the catheter in the target region;coupling the catheter to a source of the therapeutic; and delivering thetherapeutic to the target region through the catheter.

In yet another embodiment, a kit for delivering a therapeutic byconvection enhanced delivery to a location in a body comprises: a hollowguide tube comprising a lumen therethrough with distal and proximalopenings, wherein the guide tube has an outer diameter in a range of 0.5mm to 1.2 mm; a stylet, having proximal and distal portions, configuredto be disposed within the guide tube lumen, wherein the stylet distalportion is configured to extend distally from the guide tube distalopening; a catheter having a catheter lumen running from a distalopening to a proximal opening, the catheter lumen having a diameter in arange of 0.03 mm to 2.11 mm; a loop coupled to a distal portion of thecatheter and configured to be releasably coupled to the stylet distalportion; and instructions for using the hollow guide tube, stylet, andcatheter to deliver a therapeutic by convection enhanced delivery by:disposing the stylet within the guide tube lumen, and extending thestylet distal portion distally from the guide tube distal opening;releasably coupling the loop on the catheter distal portion to thestylet distal portion; distally inserting the releasably coupled tube,stylet and catheter into the body and locating the distal portion of thecatheter in a target region; withdrawing the stylet proximally throughthe tube and releasing the catheter from the stylet; withdrawing theguide tube from the body and leaving the catheter distal opening in thetarget region; coupling the catheter to a source of the therapeutic; anddelivering the therapeutic to the target region through the catheter.

In yet another embodiment, a kit for delivering a therapeutic byconvection enhanced delivery to a location in a body comprises: acatheter having a catheter lumen running from a distal opening to aproximal opening, the catheter lumen having a diameter in a range of0.03 mm to 2.11 mm; a stylet, having proximal and distal portions,configured to be disposed within the catheter lumen; and instructionsfor using the stylet and catheter to deliver a therapeutic by convectionenhanced delivery by: disposing the stylet within the catheter lumen;distally inserting the stylet and catheter into the body and locatingthe distal opening of the catheter in a target region; withdrawing thestylet proximally through the catheter lumen and leaving the catheterdistal opening in the target region; coupling the catheter to a sourceof the therapeutic; and delivering the therapeutic to the target regionthrough the catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention may be better understood byreferring to the following description in conjunction with theaccompanying drawings in which:

FIG. 1 represents a microcatheter according to one embodiment of thepresent invention;

FIGS. 2A and 2B represent an inserter and the microcatheter of FIG. 1arranged in accordance with an embodiment of the present invention;

FIG. 3 is a close-up view of a distal portion of the system shown inFIGS. 2A and 2B;

FIG. 4 is a schematic diagram showing the configuration of an array ofmicrocatheters placed within a tumor in the brain in accordance with oneembodiment of the present invention;

FIG. 5 is a method of inserting a microcatheter in accordance with oneembodiment of the present invention;

FIG. 6 is an alternate system in accordance with one embodiment of thepresent invention;

FIG. 7 is an alternate system in accordance with another embodiment ofthe present invention;

FIG. 8 is an alternate system where a fiber optic waveguide is providedin accordance with one embodiment of the present invention; and

FIG. 9 is an alternate system in accordance with another embodiment ofthe present invention.

DETAILED DESCRIPTION

The various embodiments of the invention are herein described withreference to the accompanying drawings. It is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of the various embodiments of the present invention only.These are presented in the cause of providing, what is believed to be,the most useful and readily understood description of the principles andconceptual aspects of the invention. In this regard, no attempt is madeto show structural details of the invention in more detail than isnecessary for a fundamental understanding of the invention, thedescription taken with the drawings making apparent to those skilled inthe art how the several forms and embodiments of the present inventionmay be embodied in practice.

Prior to explaining at least one embodiment of the present invention indetail, it is to be understood that the present invention is not limitedin its application to the details of construction and the arrangement ofthe components set forth in the following description or as illustratedin the drawings. The invention is capable of other embodiments or ofbeing practiced or carried out in various ways. Also, it is to beunderstood that the phraseology and terminology employed herein are forthe purpose of description and should not be regarded as limiting.

It is advantageous to be able to direct a small diameter catheter to aspecific location, e.g., a tumor in a brain, to deliver a therapeutic asthe smaller diameter minimizes backflow and, therefore, more therapeuticis delivered where needed. Small diameter catheters, however, do nothave sufficient rigidity to allow for repeatable and accurate placement.As will be described in more detail below, in various embodiments of thepresent invention, a convection enhanced delivery system (“CEDSYS”) andcorresponding method employs an array of microcatheters or micro-cannulathat can be stereotactically placed in order to distribute a therapeuticto, for example, uniform or irregularly-shaped intracerebral targets.

The term “therapeutic” is defined herein as any substance that isdeliverable using the methods described below. These substances aretypically, but not limited to, medicines in a fluid medium used to treatdisease, to restore or improve function of central nervous system (CNS)regions, i.e., tissues comprised by the brain and spinal cord, or todestroy or impair dysfunctional or rogue tissue or other material withinthe CNS. In addition, a therapeutic may comprise a capsule ormicro-capsule, powder, gel, solid, or gas.

Referring now to FIG. 1, in accordance with an embodiment of the presentinvention, a microcatheter 100 is composed of bio-compatible tubing,e.g., polyimide, with an internal diameter (ID) range of about 0.03 mmto 2.11 mm, and an outer diameter (OD) ranging from about 0.05 mm to 3mm. As known to those of ordinary skill in the art, a length of themicrocatheter 100 is sufficient to allow for connection to any equipmentneeded for the procedure. The microcatheter 100 may also be referred toas a micro-cannula, however, the terms as used herein areinterchangeable and not meant to be limiting.

A distal portion 102 of the microcatheter 100 may be impregnated with anMRI detectable or otherwise radio-opaque material to facilitate viewingand evaluation of placement. This material may be confined to the distalportion 102 of the tubing. In an alternate embodiment, the entiremicrocatheter 100 may be radio-opaque or MRI detectable. A proximal end104 of the microcatheter 100 is attached to a universal adaptor 106,e.g., a Luer fitting. A loop or ring 108 is affixed to the distalportion 102 of the microcatheter 100. The loop 108 is approximately0.5-1.5 mm in diameter, and, in one embodiment, is composed of finesuture, e.g., 6-0, 7-0, 8-0, 9-0, or 10-0 suture, or other similarmaterial. The material may be absorbable to minimize potential tissuedisruption upon removal of the microcatheter 100. Alternatively, theloop 108 may be made from an inert material, e.g., very thin stainlesssteel or the like. The loop 108 may be integral to the microcatheter 100or attached by any one of a number of ways, for example, but not limitedto, gluing, tying, and welding.

Referring now to FIG. 2A, a small-gauge stereotactic inserter or guidetube 200, e.g., an inserter similar to one produced by PreferredInstruments, Inc. is provided. The inserter 200 is composed of stainlesssteel hollow tubing with a diameter of 0.5-1.2 mm. A solid stylet 202with a rounded distal portion 204 is placed within the guide tube 200and extends beyond a distal portion 206 of the guide tube 200 byapproximately 0.5 to 1 mm. The solid stylet 202 may be a metal such as:stainless steel, platinum, cobalt, titanium, or tantalum, or similarmetal, any of which could be in either an alloy or pure form. The stylet202 may have a diameter in the range of 0.1 to 2.0 mm. In an alternateembodiment, the stylet is not solid but sufficiently stiff or resistantto bending so as to facilitate insertion as explained below.

As shown in FIG. 2B, an enlarged cross-sectional view of that shown inFIG. 2A, a proximal end 208 of the stylet 202 is fixed permanently to athumbscrew 210 that treads within a threaded portion 212 of the guidetube 200. Thus, upon turning the thumbscrew 210 the stylet 202 is movedwithin the guide tube 200.

The inserter 200 may also incorporate a stop 214 that may be moved alongthe length of the guide tube 200 and locked at any location along thelength. The stop 214 may comprise a set screw or the like. The stop 214provides an indicator to allow for precise depth placement of the guidetube 200 during a stereotactic procedure.

In accordance with one embodiment of the present invention, a method500, referring to FIG. 5, for inserting one or more microcatheters 100in, for example, the brain of a patient, will be described.

Initially, step 502, neuroimaging is performed and the patient isprepared for stereotactic surgery as known to those of ordinary skill inthe art. The preparation may include determining sites in the brain 300for microcatheter 100 placement with respect to an affected area 306.

Subsequently, or at the same time as the preparation above, themicrocatheters 100 are releasably coupled to the inserters 200 andprepared for stereotactic insertion, step 504. As shown in FIG. 3, theloop 108 at the distal portion 102 of the microcatheter 100 is placedaround the distal portion 204 of the stylet 202. The length of themicrocatheter 100 rests apposed to the inserter 200 tubing, temporarilybeing held together with the loop 108 distally and proximally by bonewax or other suitable material to fix the microcatheter 100 to the guidetube 200. This step may include prefilling the microcatheters 100 withtherapeutic and attaching them to a filled syringe 302. Alternatively,the filled microcatheter may be capped until attached to the syringe302. The system may be prepared in advance and purged of air, ifnecessary.

At step 506, one or more burr hole(s) are drilled, the dura is incised,and each microcatheter 100 is advanced, in turn, to the predeterminedtarget area 306 as directed by the inserter 200. A single burr hole mayaccommodate multiple microcatheters 100, or two or more burr holes maybe created based on the configuration of microcatheters 100 required toreach the desired targets.

The inserter 200 with the microcatheter 100 coupled, via the loop 108,to the distal portion 204 of the stylet 202 is directed, or “pushedthrough” to the target location or region. The rigidity of the inserter200 and the stylet 202 combine to “pull” the microcatheter 100 along asthe microcatheter itself is too flexible to be “pushed” through thebody, e.g., through brain matter.

At step 508, the stylet 202 is withdrawn through the inserter 200 torelease the loop 108. As above, the thumbscrew 210 is unscrewed,allowing the stylet 202 to be withdrawn proximally from within thestainless steel guide tube 200 thus releasing the microcatheter loop 108and allowing the microcatheter 100 to be positioned at the desiredlocation independently.

Once a microcatheter 100 is in the desired location, the inserter 200 iswithdrawn and the microcatheter 100 is anchored to the rim of the burrhole using, for example, a small amount of adhesive, step 510. Theadhesive produces a “spot weld” which will hold the microcatheter 100 inplace but release the microcatheter 100 when sufficient force in adirection opposite of insertion is applied at the time of microcatheter100 removal. A fast-curing, FDA-approved, silicon adhesive, or the like,may be used.

Alternatively, the surgeon can, after all the desired microcatheters 100are positioned, fill the burr hole, with an array of microcatheters 100emerging therefrom, with fibrin glue such as Tisseal, or the like.

The scalp is then closed around the microcatheters 100 using standardprocedures. The microcatheters 100 may be looped atop the patient'shead, to allow freedom of movement or “slack” in the event that themicrocatheters 100 are inadvertently pulled. The syringes 302 attachedto each microcatheter 100 are mounted into the infusion pump 304.

Alternatively, or in addition, the microcatheters 100 can be providedtogether, i.e., as a bundle, and threaded through larger-diameterflexible tubing (not shown) to provide protection to individualmicrocatheters 100.

The therapeutic is then delivered at the appropriate rate, or sequenceof rates, using the infusion pump 304, for the duration of the infusionprotocol (minutes to days), step 512. After insertion of a microcatheter100 at a desired location in, for example, a brain 300, as shown in FIG.4, the proximal end 106 is attached to a therapeutic-filled syringe 302connected to an infusion pump 304. An infusion pump 304, as known tothose of ordinary skill in the art, may be used to control the rate ofinfusion of the therapeutic. As shown in FIG. 4, multiple microcatheters100 may be inserted, each of which is connected to a respective singlesyringe 302. In an alternative embodiment, two or more microcatheters100 may be connected to the same syringe 302. In yet another embodiment,a single microcatheter 100 may be connected to multiple syringes 302,for example, in order to deliver alternate therapeutics or therapeuticsthat are combined at delivery.

Upon completion of the infusion protocol, the microcatheters 100 areremoved by applying a pulling force in the direction opposite to that ofmicrocatheter 100 entry so as to overcome the adhesive anchor at the rimof the burr hole, step 514. The anchor is the only point of fixation andis designed to release the microcatheters 100. The microcatheters 100can be removed by pulling until their entire length is withdrawn fromthe brain, exiting through the burr hole and the closed scalp incision.

The removal of the microcatheters 100 does not necessarily requirereopening the scalp incision. The decision of whether or not to open theincision, however, is up to the physician and based on the circumstancesof the case.

The systems and methods described herein are suitable for short-term,long-term, or permanent ongoing delivery of therapeutic within the brainor spinal cord including malignant or non-malignant brain tumors. Themalignant brain tumor may be one of: a tumor of the neural cells, atumor of the glial cells, or a tumor of both neural and glial cells.

Other applications may include infusion of growth factors, angiogenesisfactors, antioxidants, vectors to deliver genes, or any fluid materialto be infused within the CNS or elsewhere in the body.

Similarly, these systems and methods can be adapted for delivery oftherapeutic to virtually any other area of the body, such as internalorgans, e.g., liver, pancreas, spleen, kidney, heart, and skin. Stillfurther, tissue can be treated including, but not limited to, normaltissue, ischemic tissue, cystic tissue, neurodegenerating tissue, orotherwise diseased or dysfunctional tissue.

Infusion of therapeutics using these systems and methods may employother pumping devices as alternatives to the infusion pump described.Pumping devices may be positioned outside of the body or they may beimplanted within the body, such as subcutaneously or within a cavity,e.g., intraperitoneally. Pumping devices may be automated, may operatethrough an osmotic mechanism, e.g., mini-osmotic pump, or may becontrolled by the health care provider or the patient herself.

The microcatheter 100 may come loose from the guide tube 200 and stylet204 during insertion. It may be possible for the physician or operatorto detect that the microcatheter 100 is no longer progressing toward thetarget area due to a loss of tension on the microcatheter 100. In asituation where the tension, or loss thereof, cannot be detected byfeel, however, inaccurate placement of the microcatheter 100 may result.

Referring now to FIG. 6, in accordance with one embodiment of thepresent invention, a system 600 is provided where the tension on themicrocatheter 100 is monitored as it is being placed in position. Astrain gauge 602 is coupled, via a connector 604, to the microcatheter100 and to the stylet 202 via a connector 606. The strain gauge 602measures the tension on each of the stylet 202 and the microcatheter100. The strain gauge 602 can be set to issue an alarm if there is arelative change between the two measurements. Alternatively, the straingauge may be connected to only the microcatheter 100 and when there iseither a loss of tension detected, or the level of tension falls below apredefined threshold, an alarm indicating that, perhaps, themicrocatheter 100 has uncoupled from the stylet 202, would sound.

Referring now to FIG. 7, a system 700 provides an alternate embodiment,according to one aspect of the present invention, for determining thatthe microcatheter 100 has disconnected from the stylet 202. In thisembodiment, a loop 702 is made from stainless steel or a similarconductive material and couples the microcatheter 100 to the stylet 202.A continuity tester 704 is coupled, via a very thin wire 706 to the loop702. In addition, the continuity tester 704 is coupled, via a secondwire 708 to the thumbscrew 210 and, therefore, completes a circuitthrough the stylet 202, the loop 702, and the wire 706. If the loop 702disconnects from the stylet 202, the circuit will be broken and anindication of such, for example, an alarm, will notify the operator orphysician. The wire 706 may run down through the microcatheter 100 andbe connected to the loop 702 or the wire 706 may run along the outsideof the microcatheter 100 and connect to the loop 702.

In one embodiment, referring now to FIG. 8, in a system 800 themicrocatheter 100 is replaced by an optical waveguide 802, e.g., fiberoptic material. Similar to that shown in FIGS. 2A and 3, the waveguide802 is coupled to the guide tube 200 by the loop 108 for insertion atthe desired location. A proximal end of the waveguide 802 is coupled toa light energy source and/or camera device 804. The device 804 mayeither provide light energy through the waveguide or capture images. Thelight energy may be IR, UV or any other frequency necessary to provide,for example, photodynamic therapy or the like. The choice of materialfor the optical waveguide 802 is understood by one of ordinary skill inthe art and will depend on, among other parameters, the frequency of thelight energy to be delivered, the power of the device 804 and thedistance over which the light energy is directed.

Thus, where a plurality of microcatheters 100 are inserted, one could bean optical waveguide in order to facilitate photodynamic therapy at thedesired location. Photodynamic therapy is performed by injecting aphotoreactive agent into a tumor site, via one or more of themicrocatheters 100, and then transmitting light through the opticalwaveguide to irradiate the photoreactive agent.

In an alternate embodiment, shown in FIG. 9, the microcatheter 100contains a rigid guide 900, thus allowing the microcatheter 100 to beplaced at any depth within the brain without the need for being“piggy-backed” on the inserter. The rigid guide 900 may be a stylet, asdescribed above, in order to provide the microcatheter 100 withsufficient rigidity during insertion.

In operation, the microcatheter 100, with the rigid guide 900 within, isdirected to the target location in, for example, the brain. As above, anumber of microcatheters 100 may be provided where each is directed to adifferent location in order to provide therapeutic to the desiredtargets. Once the microcatheter 100 is fixed into position, the guide isremoved from within. Similar to the process described above, atherapeutic is delivered through the lumen of the microcatheter 100 byconnection to, for example, a syringe 302.

The microcatheter 100 of the embodiments of the present inventionprovide therapeutic via convection enhanced delivery with minimumbackflow. Further, the patient is more comfortable due to theflexibility of the catheter and its ease of positioning. Multiplemicrocatheters can be positioned to provide full coverage of thetherapeutic to one or more targeted regions. The microcatheter 100 isguided to, and positioned at, the desired location by operation of beingeither “piggy-backed” on the guide tube or by operation of a guidereleasably placed in the microcatheter lumen.

It is appreciated that certain features of the invention, which are, forthe sake of clarity, described in the context of separate embodiments,may also be provided in combination in a single embodiment. Conversely,various features of the invention, which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable subcombination.

Although various exemplary embodiments of the present invention havebeen disclosed, it will be apparent to those skilled in the art thatchanges and modifications can be made which will achieve some of theadvantages of the invention without departing from the spirit and scopeof the invention. It will be apparent to those reasonably skilled in theart that other components performing the same functions may be suitablysubstituted.

1-13. (canceled)
 14. A method of delivering a therapeutic to a targetregion in a body, the method comprising: providing a hollow guide tubecomprising a lumen therethrough with distal and proximal openings, theguide tube having an outer diameter in a range of 0.5 mm to 1.2 mm;disposing a stylet, having proximal and distal portions, within theguide tube lumen, and extending the stylet distal portion distally fromthe guide tube distal opening; providing a catheter having a distalportion and releasably coupling the catheter distal portion to thestylet distal portion, the catheter comprising a catheter lumen, thecatheter lumen having a diameter in a range of 0.03 mm to 2.11 mm andrunning from a distal opening to a proximal opening; fixedly attaching afixed diameter loop only to an exterior of the catheter at a catheterdistal portion; releasably coupling the loop to the stylet distalportion; distally inserting the releasably coupled guide tube, styletand catheter into the body and locating the distal portion of thecatheter in the target region; withdrawing the stylet proximally throughthe tube and releasing the catheter from the stylet; withdrawing theguide tube from the body and leaving the distal opening of the catheterin the target region; coupling the catheter to a source of thetherapeutic; and delivering the therapeutic to the target region throughthe catheter.
 15. The method of claim 14, wherein the loop comprises atleast one of: suture material; stainless steel; and a biologically inertmaterial.
 16. The method of claim 15, wherein fixedly attaching the loopto the catheter distal portion comprises one of: welding the loop to thecatheter; wrapping the loop around the catheter; integrating the loopwith the catheter; and gluing the loop to the catheter.
 17. The methodof claim 14, further comprising: providing a threaded portion to theguide tube; providing a threaded portion on the stylet; and threadingthe tube threaded portion to the stylet threaded portion, whereinwithdrawing the stylet comprises: turning the stylet to facilitatemovement of the stylet threaded portion with respect to the tubethreaded portion.
 18. The method of claim 14, wherein the styletcomprises at least one of: stainless steel, platinum, cobalt, titanium,tantalum, and any alloy thereof.
 19. The method of claim 14, wherein thecatheter comprises optical waveguide material to carry light energy froma proximal end to a distal end, the method further comprising: applyinglight energy to the proximal opening of the catheter and emitting thelight energy from the distal opening.
 20. The method of claim 14,wherein: the guide tube comprises a first amount of flexibility; and thecatheter comprises a second amount of flexibility, wherein the catheteris significantly more flexible than the guide tube.
 21. The method ofclaim 14, further comprising at least one of: measuring force exerted onthe catheter during an insertion procedure; and measuring force exertedon the guide tube during the insertion procedure.
 22. The method ofclaim 21, further comprising: measuring a difference between themeasured force exerted on the catheter and the measured force exerted onthe guide tube.
 23. The method of claim 14, further comprising:electrically coupling the stylet and the catheter to one another tocreate a circuit; and detecting when the circuit is opened.
 24. Themethod of claim 14, further comprising: placing therapeutic within thecatheter prior to insertion in the body. 25-39. (canceled)